ENHANCED MIDBRAIN DOPAMINE REACTIVITY TO METHYLPHENIDATE IN MARIHUANA ABUSERS Chronic marijuana abuse is clinically associated with an amotivational syndrome that may result from dysfunction of the brain DA system, which plays a central role in motivation. Here we evaluate the reactivity of the brain DA system in marijuana abusers (MA) (n=24) and normal controls (NC) (n=28) when challenged with methylphenidate (MP)(0.5 mg/kg iv) as compared to placebo using PET and 11Craclopride. Despite an attenuated behavioral and cardiovascular response to MP in MA; the DA increases in striatum were similar for both groups. In contrast, DA increases in substantia nigra (SN) and subthalamic nucleus (STN), which are regions with high concentrations of D3 receptors, were significantly greater in MA than NC. Scores on the personality measure of Positive Emotionality were lower and those of Negative Emotionality higher in MA than NC and these measures were negatively associated with MP-induced DA increases in SN and STN. These findings are consistent with an upregulation of D3 receptor signaling in SN and STN in MA that might underlie their negative emotionality. DOPAMINE INCREASES DURING STIMULANT INTOXICATION ARE MARKEDLY ATTENUATED IN COCAINE ABUSERS REGARDLESS OF PRESENCE OR ABSENCE OF CUES The ability of cocaine to increase DA is believed to underlie its rewarding effects. Pardoxically brain imaging studies show that cocaine abusers display significantly attenuated stimulant-induced DA increases. Here, we tested the hypothesis that DA hyporesponsivity in cocaine abusers reflects the lack of cocaine-cues and therefore that the concomitant administration of the stimulant drug with cocaine-cues would enhance DA increases. We studied 62 male participants (43 cocaine abusers and 19 controls) using PET and 11Craclopride to measure DA increases induced by iv MP. In 24 cocaine abusers we also compared MP when delivered concomitantly with a cocaine-cue video versus when delivered with a neutral video. MP significantly increased DA in striatum and prefrontal cortex (BA 10) in controls (p<0.001), but in cocaine abusers MP increased DA only in ventral striatum (increases associated with craving) and its effects did not differ when cocaine-cues were present or not. Compared to controls, MP effects in cocaine abusers in striatum were attenuated for both cocaine-cue and neutral- video conditions and also when given with no video stimulation (as given to controls) whereas it induced craving in abusers (for all conditions) but not in controls. Our results did not support our hypothesis and indicate that in cocaine abusers MP-induced DA increases are markedly attenuated even with cues. OVERLAP IN BRAIN ACTIVATION PATTERNS TO FOOD AND COCAINE-CUES IN COCAINE ABUSERS: ASSOCIATION TO STRIATAL D2 RECEPTORS It is hypothesized that cocaine-induced neuroadaptations hijack the DA pathways of natural reward. However, the overlap networks of natural and drug rewards are largely unknown. The study was done in 20 currently active cocaine abusers we measured D2/D3 receptor using PET with 11Craclopride and brain activation responses to neutral, food and cocaine cues using fMRI. We found that food and cocaine cues activated a common network (cerebellum, insula, inferior frontal, orbitofrontal, somatosensory and occipital cortices) and co-deactivated ventral striatum and default-mode network (DMN) regions as compared to neutral-cues. Striatal D2/D3 receptor availability was associated with activation/deactivation for both food- and cocaine-cues. Food-cues produced stronger activation than cocaine-cues in posterior insula and inferior frontal cortex, and stronger deactivation in posterior DMN regions and hypothalamus. Longer exposure to cocaine was associated with lower activation in calcarine cortex and cerebellum to both cues and liking of cues (both food and cocaine) with activation in somatosensory, cerebellum, occipital and temporal cortices to exposure to either cue. In contrast higher BMI was associated with higher activation in somatosensory and orbitofrontal cortices only to food-cues. Our results are consistent with the hypothesis that cocaine-induced neuroadaptations hijack the pathways of natural reward and indicate that DA modulates this. FUNCTIONAL CONNECTIVITY OF SUBSTANTIA NIGRA AND VENTRAL TEGMENTAL AREA: MATURATION DURING ADOLESCENCE AND EFFECTS OF ADHD Dopaminergic pathways play crucial roles in brain function and their disruption is implicated in various neuropsychiatric diseases. Here we demonstrate in 402 healthy children/adolescents (12 3 years) and 704 healthy young adults (23 5 years) that the functional connectivity of DA pathways matures significantly from childhood to adulthood in healthy children but less so in 203 children (12 3 years) with ADHD. This transition is characterized by age-related increases in the functional connectivity of the VTA with limbic regions and with the DMN and with decreases in the connectivity of the SN with motor and medial temporal cortices. The changes from a predominant influence of SN in childhood/adolescence to a combined influence of SN and VTA in young adulthood might explain the increased vulnerability to psychiatric disorders, such as ADHD, early in life. We also show that VTA and SN connectivity networks were highly reproducible. THE ENERGETIC COST OF BRAIN FUNCTIONAL CONNECTIVITY The brain's functional connectivity has high energetic cost and requires efficient use of glucose. It has been proposed that regions with high degree of functional connectivity are energy-efficient and can minimize consumption of glucose. The relationship between functional connectivity and brain energy consumption is poorly understood. To address this, here we propose a simple model for the energy demands of brain functional connectivity, which we tested with PET and MRI in 54 controls at rest. Higher glucose metabolism was associated with larger MRI signal amplitudes, and a higher degree of connectivity was associated with non-linear increases in metabolism. Basal metabolism (in absence of connectivity) accounted for 30% of brain glucose utilization, which suggests that the spontaneous brain activity accounts for 70% of the energy consumed by the brain. The energy-efficiency of the connectivity hubs was higher for ventral precuneus, cerebellum and subcortical hubs than for cortical hubs. The higher energy demands of brain communication that hinges upon higher connectivity could render hubs more vulnerable to deficits in energy delivery or utilization and help explain their sensitivity to neurodegenerative conditions (Alzheimers disease). FUNCTIONAL CONNECTIVITY AND BRAIN ACTIVATION: A SYNERGISTIC APPROACH Traditional fMRI studies exploit endogenous brain activity for mapping brain activation during periodic cognitive/emotional challenges or brain functional connectivity during the resting-state (RSFC). We hypothesized that these modalities can be synergistically complemented by functional connectivity measures during a continuous task-state (TSFC). Forty-five controls underwent standard RSFC, as well as TSFC during a continuous visual attention (VA) task, and standard fMRI with a blocked version of the VA task at 4Tesla. High-resolution data-driven functional connectivity density (FCD) mapping was used to measure task-related connectivity changes without a-priori hypotheses. Task performance was associated with decreased FCD in regions activated/deactivated by the task, and performance accuracy increased with decreased FCD in these regions. Thus, improved performance might reflect lower connectivity and interference of task-irrelevant regions during the task.